Field of the Invention
The invention relates to the detection of a possible loss of integrity of a closed, non-porous, flexible plastic pouch, such as a sterile pouch that is designed to accommodate a biopharmaceutical product or device or the like.
The purpose of the invention is more especially a pouch with an incorporated loss of integrity indicator that is active per se, and, after the pouch is manufactured and at least before the time when a biopharmaceutical product or device is to be introduced thereinto, the application of such a pouch with an incorporated and active loss of integrity indicator for creating a pouch stricto sensu that has all of its integrity and that contains the biopharmaceutical product or device, with such a pouch stricto sensu having its full guarantee of integrity, specially designed to contain a biopharmaceutical product or device, a process for the production of a pouch with an incorporated and active loss of integrity indicator, and, finally, a process relative to pouches stricto sensu that is specially designed to contain a biopharmaceutical product or device and having to exhibit a full guarantee of integrity.
Description of the Related Art
Here, a biopharmaceutical product is defined as a product that is obtained from biotechnology—culture media, cellular cultures, buffer solutions, artificial nutrition liquids, blood products, and derivatives of blood products—or a pharmaceutical product or more generally a product that is designed to be used in the medical field. Biopharmaceutical device is defined as a device that is designed to be implemented in a process of the biological or pharmaceutical field—measuring or checking means, means for treatment of a biopharmaceutical product, containers or parts of containers, means of transfer or closing. Such biopharmaceutical products or devices have high added value, and it is important that their integrity be ensured, in particular the absence of any contamination.
For the purposes of storage or shipping, it is common to place such biopharmaceutical products or devices in pouches that are closed and sterile, flexible, disposable, and made of non-porous plastic (such as polyethylene or a complex that comprises polyethylene) and that comprise at least one port or access that can be opened at the desired time.
Such pouches are known whose two large walls are directly joined to one another. Once expanded, such pouches have a limited volume and are relatively thin, which justifies the fact that they are often called “pillow” pouches or “2D” (D meaning dimensions) pouches. 3D pouches are also known that comprise two end walls and a side wall that can be folded flat and deployed unfolded, welded to one another, with the volume then being able to be at least 50 liters up to 3,000 liters, and even more. Such 3D pouches are described in the document WO00/04131 or marketed by the Sartorius Company under the trademark FLEXEL® 3D.
It is essential that such pouches, once manufactured and when they receive the biopharmaceutical products or devices mentioned above, be airtight, or at least have a degree of sealing that is deemed satisfactory. It is therefore essential to be able to detect any possible loss of integrity of such pouches.
Processes and devices for checking integrity of such pouches implemented online on all of the pouches during their manufacturing are known. Thus, the Standard F 2095-01 of ASTM International whose title is “Standard Test Methods for Pressure Decay Leak Test for Nonporous Flexible Packages with and without Restraining Plates” relates more specifically to the so-called pressure drop process. This process is considered according to two possible embodiments, namely with or without expansion-limiting plates.
In the embodiment with expansion-limiting plates, the procedure is as follows:                In a preparation phase:                    A pouch to be checked that has at least one port that can be sealed or connected in an airtight and removable way is provided,            A pressurized gas source that is designed to be introduced into the pouch via the port is provided,            Means for measuring the pressure of the gas in the pouch via the port are provided,            Two fixed expansion-limiting plates that are separated and face one another and that will not conceal a possible leak in the large walls of the pouch placed against them are provided,            The pouch is placed flat between the two expansion-limiting plates,            At least one port of the pouch is connected to the gas source and the pressure-measuring means in such a way as to be able to send the pressurized gas into the pouch and to measure the pressure of the gas in the pouch,                        And, in a subsequent test phase:                    The pressurized gas is sent into the pouch, with the expansion of the pouch being limited when its large walls come against the expansion-limiting plates,            Then, in a subsequent stage, the pressure drop in the pouch owing to the pressure-measuring means is compared to a predefined pressure drop threshold of a pouch that is considered intact.                        
If the pressure drop in the pouch is less than the threshold, it is considered that the pouch has passed the integrity check, while if the pressure drop in the pouch is greater than the threshold, it is considered that the pouch has not passed the integrity check.
Devices for implementing a checking process for filters and membranes, by the pressure drop technique, without expansion-limiting plates, for example the device SARTOCHECK® 4 of the SARTORIUS Company, are known. Devices with plates from other suppliers are known. In all of the cases, such devices are complex and bulky and difficult to ship or to use at the sites of final use of the pouches.
In contrast, an accidental rupture of the integrity of the pouch can occur after its manufacture and before its final use, for example in the phases of storage, shipping, distribution, delivery or else in the phase that immediately precedes the implementation of the pouch. This risk is all the greater the longer any of these phases lasts (for example, the storage phase can reach several years) or if it involves handling of the pouch or its contact with objects that will promote damage thereof. However, such a rupture of the integrity of the pouch cannot be decelerated by a process for checking integrity that is implemented before the integrity rupture takes place.
The documents U.S. Pat. Nos. 6,892,567 and 6,196,056 describe processes and devices for determining the integrity of a package or a compartment resting on the transmission of a test gas through the package or the wall of the compartment. This device and the associated measuring instruments form a complex and bulky unit having the limitations mentioned above.
The document US 2007/0220956 describes a process and a device for detecting a leak from a pouch designed for the production of a process that is biological and that contains a conductive fluid, placed in a rigid outer container, consisting of an electrically-operated leak detector. Such a process and device exhibit the same limitations mentioned above, unless they are applied in the case of a pouch that is filled with a conductive fluid and ultimately involve the presence of a rigid outer container.
The document U.S. Pat. No. 4,098,577 describes a process and an indicator for detecting the loss of integrity of transparent packaging that contains a product that is sealed in the packaging. The packaging is filled with an artificial atmosphere such as carbon dioxide or nitrogen. A pH-sensitive detector is placed in the packaging and can be seen through it. The detector changes color in the case of a loss of artificial atmosphere as a result of a loss of integrity of the packaging. In the embodiments considered by the document U.S. Pat. No. 4,098,577, the packaging is rigid, the product is a solid object, and the detector is moved away from the latter. The process according to the document U.S. Pat. No. 4,098,577 is unsuitable in the case of packaging that is designed to accommodate a fluid product coming into contact with the detector. In addition, the document U.S. Pat. No. 4,098,577 neither describes nor suggests, indeed quite the contrary, that the detection takes place before the product is placed in the packaging.
The document U.S. Pat. No. 4,813,541 describes a process and packaging with a tamper-proof indicator. The packaging comprises a first hermetically sealed, rigid, inner container filled with a first atmosphere and containing a substance, and a second hermetically sealed, rigid, outer container in which there is located—in a spaced position owing to crosspieces—the first container, the inner cavity of the second container outside of the first container being filled with a second atmosphere at a pressure that is different from that of the first atmosphere, and detection means being placed in the cavity and being sensitive to a modification of the second atmosphere due to a rupture of integrity of the first container or the second container. The document U.S. Pat. No. 4,813,541, which describes a very particular structure, does not suggest that the detection take place before the substance is placed in the first container.
The document WO 01/04624 describes a colorimetric system that comprises a detector that is sensitive to carbon dioxide.
The document WO96/12659 describes a so-called tamper-proof packaging that comprises an inner membrane that delimits an inner compartment, which contains a first medium that consists of air, as well as an outer membrane that delimits an outer compartment that surrounds the inner compartment and contains a second medium that consists of carbon dioxide. An indicator tab, sensitive to the surrounding environment, is provided inside the outer compartment, and it can give an indication relative to a change in the first medium and in the second medium.
The document U.S. Pat. No. 4,434,893 describes a packaging for accommodating products that comprise inner and outer cases. In one embodiment, the inner case and the outer case respectively have only a single flexible wall, and these inner and outer cases are pressurized using a gas that has a pressure that is higher than the atmospheric pressure in such a way as to inflate their flexible wall. In another embodiment, the two walls of each of the inner and outer cases are flexible. The products—capsules, gel capsules or the like—to be protected are included inside the inner case, and the inner case is itself located in this outer case in such a way as to form a protection preventing access to the products.
The document U.S. Pat. No. 4,436,203 describes a packaging that comprises an inner container of predefined size, filled with a product and pressurized before being arranged inside an outer container. After its inner pressure has dropped below the atmospheric pressure, said outer container is closed. Thus, when one of the walls of the packaging is pierced, the consumer is alerted because the product may have been touched.
The document FR 2 252 619 describes a device that is designed to be used with a packaging that is normally closed hermetically. It comprises a detector that is arranged in such a way that it is in communication with the interior of the packaging but also visible from the outside. This detector contains a pH-sensitive dye, which has a first color at a normal atmospheric pH and a second color at a pH that is slightly greater than or less than the normal atmospheric pH.
The invention therefore has as its object to eliminate the above-mentioned problems by proposing to detect the rupture of integrity of a pouch—at any desired time after its manufacture and in any case just before its use by installation in the pouch of contents that can be fluid and that come into contact with the inner surface of the pouch—in a reliable, easy and quick way, without the necessity for a heavy or complex dedicated device, or difficult or delicate operations, without the necessity of having to resort to specialized personnel especially and exclusively dedicated to checking the integrity, and without the necessity of having to test the pouch positively to ensure its integrity, the loss of integrity being revealed automatically and therefore without the necessity, when the pouch is part of a large number of pouches, of having to test each pouch positively.